Biomedical subjects

E Masliah

Publications and source records attributed to E Masliah.

At least 55 records · Page 3Linked to original sources

PubMed2001

TGF-beta1 promotes microglial amyloid-beta clearance and reduces plaque burden in transgenic mice.

Abnormal accumulation of the amyloid-beta peptide (Abeta) in the brain appears crucial to pathogenesis in all forms of Alzheimer disease (AD), but the underlying mechanisms in the sporadic forms of AD remain unknown. Transforming growth factor beta1 (TGF-beta1), a key regulator of the brain's responses to injury and inflammation, has been implicated in Abeta deposition in vivo. Here we demonstrate that a modest increase in astroglial TGF-beta1 production in aged transgenic mice expressing the human beta-amyloid precursor protein (hAPP) results in a three-fold reduction in the number of parenchymal amyloid plaques, a 50% reduction in the overall Abeta load in the hippocampus and neocortex, and a decrease in the number of dystrophic neurites. In mice expressing hAPP and TGF-beta1, Abeta accumulated substantially in cerebral blood vessels, but not in parenchymal plaques. In human cases of AD, Abeta immunoreactivity associated with parenchymal plaques was inversely correlated with Abeta in blood vessels and cortical TGF-beta1 mRNA levels. The reduction of parenchymal plaques in hAPP/TGF-beta1 mice was associated with a strong activation of microglia and an increase in inflammatory mediators. Recombinant TGF-beta1 stimulated Abeta clearance in microglial cell cultures. These results demonstrate that TGF-beta1 is an important modifier of amyloid deposition in vivo and indicate that TGF-beta1 might promote microglial processes that inhibit the accumulation of Abeta in the brain parenchyma.

Aged↗

PubMed2001

The National NeuroAIDS Tissue Consortium: a new paradigm in brain banking with an emphasis on infectious disease.

The National NeuroAIDS Tissue Consortium (NNTC) was founded in 1998, in response to the scientific need for well-characterized central nervous system (CNS) and peripheral nervous system (PNS) tissues and fluids from HIV-infected individuals. In addition to performing the routine functions of non-transplant anatomic tissue banks, the Consortium offers a unique model for the integration of independent research entities in order to provide well-characterized tissues and fluids for the international research community. Herein, we describe the structure of the Consortium, pointing out the inherent strengths of linking together multiple independent sites for the purpose of banking HIV-infected nervous system tissues. We describe the neuropathology protocol that was adopted and successfully implemented at the four participating banks of the Consortium.

AIDS Dementia Complex↗

PubMed2001

Locally reduced levels of acidic FGF lead to decreased expression of 28-kda calbindin and contribute to the selective vulnerability of the neurons in the entorhinal cortex in Alzheimer's disease.

Recent studies demonstrate that a disturbed calcium-homeostasis leading to increased susceptibility to excitotoxic triggers plays a major role in the neurodegenerative process initiating in layer 2 of the entorhinal cortex (EC2) during Alzheimer's disease (AD). Thus, proteins binding free Ca++ (i.e. calbindin) and factors regulating these proteins are of great importance for the neuroprotective-neurotoxic balance in the affected brain regions. In the present combined human and in vitro study evidence is provided that altered levels of the acidic fibroblast growth factor (aFGF) and calbindin expression are concomitantly present in EC2 neurons and have interactive effects. A dramatic loss of aFGF- and calbindin-labeled EC2 neurons was found. Further analysis of the surviving EC2 neurons revealed a strong immunoreactivity to calbindin and aFGF. In vitro experiments show that aFGF regulates calbindin expression, because treatment of differentiating neurons with recombinant aFGF increases calbindin expression in a time-dependent fashion. The data imply that a reduced expression of aFGF in EC2 neurons of AD brains leads to lower levels of calbindin resulting in decreased neuroprotective capacity.

Aged↗

PubMed2001

The placenta in multiple pregnancy: outstanding issues.

The present paper reviews the placental development in multiple gestations and highlights the twin-to-twin transfusion syndrome, its recognition and possible therapy, and some of the consequences of fetal death of one twin. It presents data on discordance for structural anomalies in monozygotic twins. These aspects are discussed with respect to their possible pathogenetic origins.

Anencephaly↗

PubMed2001

Amelioration of neurotoxic effects of HIV envelope protein gp120 by fibroblast growth factor: a strategy for neuroprotection.

Approximately two thirds of patients with human immunodeficiency virus encephalitis (HIVE) show cognitive impairment and neurodegeneration, while one third are cognitively unimpaired and their neuronal populations are preserved. Thus, it is possible that these individuals might have the capacity to produce neurotrophic factors capable of protecting neurons against the deleterious effects of HIV. In this context, the main objective of this study was to determine whether fibroblast growth factor 1 (FGF1) is protective against HIV. For this purpose levels of FGF1 immunoreactivity were determined in the frontal cortex of 35 AIDS cases subdivided into 4 groups according to the presence or absence of HIVE and neurodegeneration. In cases without both HIVE and neurodegeneration, mild to moderate levels of FGFI immunoreactivity were observed in pyramidal neurons, while in cases with HIVE but without neurodegeneration, levels were significiantly elevated. In contrast, individuals with both HIVE and neurodegeneration showed low levels of neuronal FGF1 immunoreactivity. Furthermore, studies in primary human neuronal cultures treated with the HIV envelope protein-gp120 in the presence or absence of FGF1 showed that FGF1 was protective against gpl20 neurotoxicity in a dose-dependent manner. Taken together, these results support the notion that upregulation of certain neurotrophic factors, such as FGF1, might protect the central nervous system from the neurotoxic effects of HIV.

AIDS Dementia Complex↗

PubMed2001

Neurofibrillary pathology in transgenic mice overexpressing V717F beta-amyloid precursor protein.

Overexpression of mutated human amyloid precursor protein (hAPP717V-->F) under control of the platelet-derived growth factor promoter (PDAPP minigene) in transgenic (tg) mice results in plaque formation and astroglial activation similar to Alzheimer disease (AD). However, the extent of the neurofibrillary pathology in this model is less understood. In order to determine if these mice develop AD-like neurofibrillary pathology, vibratome sections from PDAPP tg mice (4- to 20-months-old) were immunolabeled with antibodies against phosphorylated tau (AT8) and phosphorylated neurofilaments (SMI 312, TA51), and analyzed by laser scanning confocal and electron microscopy. Phosphorylated neurofilament-immunoreactive dystrophic neurites in plaques were first seen in mice at 10 to 12 months of age, while phosphorylated tau-immunoreactive dystrophic neurites were observed after 14 months of age. Immunoelectron microscopic analysis revealed that phosphorylated neurofilament immunoreactivity was diffusely distributed along filamentous aggregates (12-15 nm in diameter) in the plaque dystrophic neurites, and occasionally in neuronal cell bodies. In contrast, phosphorylated tau immunoreactivity was observed as clusters distributed along filamentous structures accumulating in the dystrophic neurites and around neurotubules in the axons. However, no paired helical filaments were observed. Taken together, these studies indicate that the PDAPP tg model recapitulates early cytoskeletal pathology similar to that observed in AD.

Alzheimer Disease↗

PubMed2001

Severe alveolar proteinosis following chemotherapy for acute myeloid leukemia in a lung allograft recipient.

A 64-year-old man was diagnosed with acute myeloid leukemia (AML) 5 years following single lung transplantation performed for severe pulmonary hypertension from scleroderma. Chemotherapy for treatment of AML with fludarabine, cytosine arabinoside, G-CSF (FLAG) regimen was initiated. Despite intensive antibiotic treatment for a presumptive diagnosis of bacterial pneumonia, the patient developed acute respiratory failure and died before a complete cycle of chemotherapy could be administered. At autopsy, both native and allograft lungs showed widespread alveolar proteinosis that was determined as the main cause of acute respiratory failure. Alveolar proteinosis, a potentially treatable disease, should be considered in the radiologic differential diagnosis of diffuse lung disease in this clinical setting.

Antineoplastic Combined Chemotherapy Protocols↗

PubMed2001

Crosstalk between components of the blood brain barrier and cells of the CNS in microglial activation in AIDS.

During the progression of AIDS, a majority of patients develop cognitive disorders such as HIV encephalitis (HIVE) and AIDS dementia complex (ADC), which correlate closely with macrophage infiltration into the brain and microglial activation. Microglial activation occurs in response to infection, inflammation and neurological disorders including HIVE, Alzheimer's disease, Parkinson's disease and multiple sclerosis. Microglia can be activated by immunoreactive cells independent of, but enhanced by HIV infection, from at least two routes. Activation may occur from signals originating from activated monocytes and lymphocytes in the blood stream, which initiate a cascade of stimuli that ultimately reach microglia in the brain or from activated macrophages/microglia/astrocytes within the brain. Effects of microglial activation stemming from both systemic and CNS HIV infection act together to commence signaling feedback, leading to HIVE and increased neurodegeneration. Most recent data indicate that in AIDS patients, microglial activation in the brain with subsequent release of excitotoxins, cytokines and chemokines leads to neurodegeneration and cognitive impairment. Since the presence of HIV in the brain results from migration of infected monocytes and lymphocytes across the vascular boundary, the development of novel therapies aimed at protecting the integrity of the blood brain barrier (BBB) upon systemic HIV infection is critical for controlling CNS infection.

AIDS Dementia Complex↗

PubMed2000

Early brain injury in the SIV-macaque model of AIDS.

OBJECTIVE: To specify the type and severity of cellular damage in the central nervous system soon after infection and at later stages of disease in the SIV-macaque model of AIDS. DESIGN AND METHODS: Adjacent samples of frontal cortical gray matter were taken from three groups of macaques: uninfected controls (n = 4), acute (14 days post-infection; n = 4), and chronic (mean 2 years post-infection; n = 7). In vitro high resolution magnetic resonance spectroscopy of snap frozen intact tissue and quantitative neuropathology measurements of synaptophysin, calbindin, and glial fibrillary acidic protein (GFAP) in formalin-fixed tissue were performed. RESULTS: Losses in n-acetylaspartate and calbindin (indicating neuronal injury and/or death) and decreases in synaptophysin immunoreactivity (indicating synaptodendritic injury) were detected along with increases in GFAP (indicating reactive gliosis). Cellular injury worsened progressively with increased time after infection. CONCLUSIONS: These results are the first direct evidence that neuronal injury occurs soon after infection. The exacerbation of injury with time suggests a connection between the early response of the central nervous system and dementia, which occurs late in the course of infection. This connection may have broad implications for the study of and the development of therapies for damage of the central nervous system by HIV.

AIDS Dementia Complex↗

PubMed2000

Unequal expression of allelic kainate receptor GluR7 mRNAs in human brains.

We describe here the first example of an exonic polymorphism that affects the primary structure of a human ionotropic glutamate receptor. The human kainate receptor GluR7 gene contains a thymine (T)/guanine (G) nucleotide variation that determines a serine or alanine at position 310 in the extracellular region of GluR7 receptor subunits. Our finding contrasts with a previous report that suggested that GluR7 transcripts were RNA-edited at this site. Whole-cell patch-clamp recordings did not detect differences in receptor activation and desensitization between the human GluR7 receptor isoforms expressed in HEK-293 cells. Analysis of 41 tissue samples obtained from 30 human brains revealed expression level differences between GluR7 alleles expressed in the same brain. The expression level of the allelic GluR7 mRNAs differed in 27 samples from 1.2- to 12.7-fold. Unequal expression level of allelic mRNAs is characteristic for genes that are affected by genomic imprinting or that contain mutations. Genomic imprinting in most cases is conserved between human and mice. However, we did not detect unequal expression of allelic GluR7 mRNAs in mice. Our results are important for future studies that explore a potential role or roles for GluR7 receptors in the brain and for neurological disorders.

Alleles↗

PubMed2000

The decline in synapses and cholinergic activity is asynchronous in Alzheimer's disease.

OBJECTIVE: To determine the timing of cholinergic loss and reduction of synapses in AD. BACKGROUND: Decrements in neocortical synapses and cholinergic function occur in AD and correlate with cognitive decline. However, how early in the disease process these changes appear remains unclear. METHODS: An autopsy series of 89 demented patients with pathologically confirmed AD (National Institute on Aging and Consortium to Establish a Registry for Alzheimer's Disease criteria) and 18 normal control subjects (NC). The AD cases were stratified according to their last Mini-Mental State Examination (MMSE) score prior to death as mild (MMSE = 20; n = 14), moderate (MMSE = 10 to 19; n = 20), severe (MMSE = 1 to 9; n = 29), and very severe (MMSE = 0; n = 26). Midfrontal (MF) synapse density was assessed by dot-immunobinding assay for synaptophysin (Syn), and MF choline acetyltransferase (ChAT) activity was determined using standard protocols. RESULTS: Compared with those in NC, neither Syn nor ChAT was appreciably reduced in patients with mild AD at death. Decline of ChAT was significant only in AD patients who died in the late stages of the disease and was maximal in those who had more severely deteriorated. In contrast, decline of Syn was significant and almost maximal in patients in intermediate or moderate stages. Consequently, the last MMSE score prior to death correlated more strongly with ChAT than Syn when the AD cohort included more impaired patients (r = 0.46 versus 0.40). The reverse occurred when only less impaired patients (MMSE = 10) were included in the analyses (r = 0.28 versus 0.64). There was only a modest correlation between Syn and ChAT activity. CONCLUSIONS: The results imply an asynchronous pattern of decline of synapses and cholinergic activity, with Syn loss preceding ChAT decrements. However, neither MF synapse reduction nor cholinergic dysfunction appears to be an early event in AD.

Aged↗

PubMed2000

A protective role of the low density lipoprotein receptor-related protein against amyloid beta-protein toxicity.

In order to delineate the neuroprotective role of the low density lipoprotein receptor-related protein (LRP) against amyloid beta-protein toxicity, studies were performed in C6 cells challenged with amyloid beta-protein in the presence or absence of activated alpha(2)-macroglobulin. Toxicity was assessed via two cell viability assays. We found that this endocytic receptor conferred protection against amyloid beta-protein toxicity in the presence of activated alpha(2)-macroglobulin and its down-regulation via inhibition by receptor-associated protein or transfection of cells with presenilin 1, increased susceptibility to amyloid beta-protein toxicity. Increased surface LRP immunoreactivity in response to amyloid beta-protein challenge was associated with increased translocation of LRP from the endoplasmic reticulum to the surface, rather than from increased mRNA or protein expression. Furthermore, this translocation of LRP to the surface was mediated by a calcium/calmodulin protein kinase II-dependent signaling pathway. These studies provide evidence for a protective role of LRP against amyloid beta-protein toxicity and may explain the aggressive nature of presenilin-1 mutation in familial Alzheimer's disease.

Alzheimer Disease↗

PubMed2000

LDL receptor-related protein (LRP) in Alzheimer's disease: towards a unified theory of pathogenesis.

To date, mutations in three genes, beta-amyloid precursor protein (APP), presenilin 1 (PS1), and presenilin 2 (PS2), have been found to be causally related to familial Alzheimer's disease (AD). In addition, polymorphisms in three other genes (among others), apolipoprotein E (apoE), alpha2-macroglobulin (alpham), and the low density lipoprotein receptor-related protein (LRP), are implicated to contribute to AD pathogenesis. Interestingly, the encoded gene products are all functionally related in various ways to LRP. Specifically apoE, alpha2m, secreted APP, and amyloid beta-protein (Abeta) complexed to either apoE or alpha2m are ligands of LRP. Furthermore, over-expression of presenilin 1 results in decreased expression of LRP. Since levels of many LRP ligands are increased in Alzheimer's disease and LRP and its ligands are present in senile plaques, decreased LRP function may be a central component in AD pathogenesis. This review explores the current knowledge of LRP in AD and its relationship to the other known AD susceptibility markers.

Alzheimer Disease↗

PubMed2000

High-level neuronal expression of abeta 1-42 in wild-type human amyloid protein precursor transgenic mice: synaptotoxicity without plaque formation.

Amyloid plaques are a neuropathological hallmark of Alzheimer's disease (AD), but their relationship to neurodegeneration and dementia remains controversial. In contrast, there is a good correlation in AD between cognitive decline and loss of synaptophysin-immunoreactive (SYN-IR) presynaptic terminals in specific brain regions. We used expression-matched transgenic mouse lines to compare the effects of different human amyloid protein precursors (hAPP) and their products on plaque formation and SYN-IR presynaptic terminals. Four distinct minigenes were generated encoding wild-type hAPP or hAPP carrying mutations that alter the production of amyloidogenic Abeta peptides. The platelet-derived growth factor beta chain promoter was used to express these constructs in neurons. hAPP mutations associated with familial AD (FAD) increased cerebral Abeta(1-42) levels, whereas an experimental mutation of the beta-secretase cleavage site (671(M-->I)) eliminated production of human Abeta. High levels of Abeta(1-42) resulted in age-dependent formation of amyloid plaques in FAD-mutant hAPP mice but not in expression-matched wild-type hAPP mice. Yet, significant decreases in the density of SYN-IR presynaptic terminals were found in both groups of mice. Across mice from different transgenic lines, the density of SYN-IR presynaptic terminals correlated inversely with Abeta levels but not with hAPP levels or plaque load. We conclude that Abeta is synaptotoxic even in the absence of plaques and that high levels of Abeta(1-42) are insufficient to induce plaque formation in mice expressing wild-type hAPP. Our results support the emerging view that plaque-independent Abeta toxicity plays an important role in the development of synaptic deficits in AD and related conditions.

Aging↗

PubMed2000

Megacystis microcolon intestinal hypoperistalsis syndrome: bladder distension and pyelectasis in the fetus without anatomic outflow obstruction.

We report a case of a 46,XY male infant with a history of normal amniotic fluid levels who was delivered by elective cesarean section at 38.5 weeks' gestation because of progressive bladder distension, hydroureteronephrosis, and what was thought to be a dilated posterior urethra. The child died at 19 days of age of cardiovascular complications. The autopsy revealed megacystis, bilateral megaureters and pyelocaliectasis, congenital absence of ganglion cells in the bladder wall, renal dysplasia, and a microcolon. No dilation or anatomic obstruction of the posterior urethra was found. These findings strongly suggest the diagnosis of megacystis microcolon intestinal hypoperistalsis syndrome. We discuss the ultrasound findings of in utero bladder distension with hydronephrosis and one of its rare etiologies.

Abnormalities, Multiple↗

PubMed2000

Fibroblast growth factor modulates HIV coreceptor CXCR4 expression by neural cells. HNRC Group.

Recent studies suggest that the chemokine receptor CXCR4 may be involved in mediating the neurodegenerative process in the brains of patients with acquired immunodeficiency disease (AIDS). In this context, we hypothesize that neurotrophic factors, such as fibroblast growth factor (FGF), might protect against human immunodeficiency virus (HIV)-mediated neurotoxicity via regulating the expression of CXCR4 in neural cells. For this purpose, levels of CXCR4 were determined in neuronal and glial cell lines after FGF1 and 2 treatment. In addition, levels of CXCR4 immunoreactivity were associated with levels of FGF1 immunoreactivity in the brains of HIV-positive patients. These studies showed that neuronal CXCR4 levels decreased in a dose-dependent manner after exposure to FGF. Conversely, glial CXCR4 was increased in a dose-dependent manner after FGF2 treatment. These effects were dependent on the FGF receptor tyrosine kinase signaling pathway, because FGF-induced effects on CXCR4 were blocked by the tyrosine kinase inhibitor, 5'-deoxy-5'methylthioadenosine, or by anti-FGF receptor antibody. Stromal cell-derived factor-1, the ligand for CXCR4, and HIV gp120 neurotoxicity was attenuated by FGF1 in a dose-dependent manner in vitro, further supporting physiological relevance. In the brains of AIDS patients, the levels of neural CXCR4 immunoreactivity were inversely associated with FGF levels. Taken together, these results support the possibility that the neuroactive effects of FGF in HIV encephalitis might be mediated through regulation of the expression of CXCR4.

Acquired Immunodeficiency Syndrome↗

PubMed2000

Dopaminergic loss and inclusion body formation in alpha-synuclein mice: implications for neurodegenerative disorders.

To elucidate the role of the synaptic protein alpha-synuclein in neurodegenerative disorders, transgenic mice expressing wild-type human alpha-synuclein were generated. Neuronal expression of human alpha-synuclein resulted in progressive accumulation of alpha-synuclein-and ubiquitin-immunoreactive inclusions in neurons in the neocortex, hippocampus, and substantia nigra. Ultrastructural analysis revealed both electron-dense intranuclear deposits and cytoplasmic inclusions. These alterations were associated with loss of dopaminergic terminals in the basal ganglia and with motor impairments. These results suggest that accumulation of wild-type alpha-synuclein may play a causal role in Parkinson's disease and related conditions.

Animals↗

PubMed2000

E4 allele dosage does not predict cholinergic activity or synapse loss in Alzheimer's disease.

OBJECTIVE: To investigate the relationship between apolipoprotein E (APOE) genotype and both cholinergic dysfunction and synapse loss in AD. BACKGROUND: A reduction in neocortical synapses and marked losses in the cholinergic system occur in AD. It has been suggested that the number of APOE epsilon4 alleles is inversely related to choline acetyltransferase (ChAT) activity, thereby influencing cholinergic function. Whether APOE genotype may influence neocortical synapse loss remains unclear. METHODS: An autopsy series of 182 patients with AD (National Institute on Aging and Consortium to Establish a Registry for Alzheimer's Disease criteria) and 16 normal controls (NC). APOE genotype was determined in blood samples or in postmortem brain tissue. Midfrontal synapse counts (AU/microg) were quantified by a dot-immunobinding assay for synaptophysin (Syn). Midfrontal ChAT activity (nmol/h/100 mg) was assessed using standard assays. RESULTS: Mean midfrontal ChAT activity and Syn were both significantly reduced in patients with AD compared with NC. The relationship between ChAT activity and number of epsilon4 allele copies in AD was complex, with ChAT activity lower in patients with either two or no epsilon4 alleles compared with those with one epsilon4 allele. There was no relationship between APOE genotype and synapse loss in AD. Syn density was almost identical across the three genotypes. CONCLUSIONS: Unlike other studies, we failed to detect a linear relationship between ChAT activity and number of epsilon4 allele copies in the midfrontal cortex of this large sample of patients with AD. Our data also show that the presence of epsilon4 allele does not influence midfrontal synapse loss in AD. This suggests that factors other than APOE genotype may be operative in the decline in midfrontal cholinergic function and synapses seen in AD.

Aged↗